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Publications

Journal Article Ppublish

PubMed: 41399249 DOI: 10.1002/alz.70989

Detection of TDP-43 seeds in CSF of presymptomatic and symptomatic genetic FTD/ALS.

Alzheimers Dement 21(12):e70989

Authors: Ilaria Linda Dellarole, Vittoria Aprea, Marcella Catania, Claudia Battipaglia, Aurora Romeo, Cristina Villa, Anna Burato, Luigi Celauro, Eleonora Dalla Bella, Nilo Riva, Erika Salvi, Giacomina Rossi, Giuseppe Di Fede, Giuseppe Legname, Julie F H De Houwer, Antonella Alberici, Barbara Borroni, Harro Seelaar, John C van Swieten, Fabio Moda, Paola Caroppo

Affiliations

  • SSD Laboratory Medicine-Laboratory of Clinical Pathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • Neurology 8 - Dementias and degenerative diseases of CNS Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore Di Studi Avanzati (SISSA), Trieste, Italy.
  • Neurology 3 - Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • Data Science Center and Computational multi-Omics of Neurological Disorders (MIND) Lab, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • Department of Neurology and Alzheimer Centre, Erasmus MC University Medical Centre (Erasmus MC), Rotterdam, The Netherlands.
  • Department of Continuity of Care and Frailty, ASST Spedali Civili Brescia Hospital, Brescia, Italy.
  • Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
  • Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
  • Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.

Abstract

INTRODUCTION

Seed amplification assays (SAAs) have shown promising results in detecting misfolded transactive response (TAR) DNA-binding protein 43 (TDP-43) in cerebrospinal fluid (CSF) of genetic frontotemporal dementia (FTD). To date, the use of SAA has yet to be evaluated in presymptomatic individuals.

METHODS

Thirty patients carrying GRN or C9orf72 mutations, 2 microtubule-associated protein tau (MAPT) carriers, 14 presymptomatic subjects, and 27 controls underwent CSF collection. We used SAA for detecting misfolded TDP-43 (TDP-43_SAA) and single molecule array (SIMOA) technology for neurofilament light chain (NfL) dosage.

RESULTS

TDP-43 seeding activity was detected in 67% of TDP-43-linked symptomatic patients, with a specificity of 93%. Almost half of presymptomatic subjects tested positive, mostly GRN carriers. Interestingly, among TDP-43_SAA positive presymptomatic individuals, two GRN carriers underwent phenoconversion.

DISCUSSION

TDP-43_SAA can also detect misfolded TDP-43 in the CSF of presymptomatic individuals. A possible link exists between positive TDP-43_SAA and conversion to the symptomatic phase.

HIGHLIGHTS

Seed amplification assay of transactive response (TAR) DNA-binding protein 43 (TDP-43_SAA) can detect misfolded TDP-43 in the cerebrospinal fluid (CSF) of patients with genetic frontotemporal dementia (FTD), linked to GRN and C9orf72 mutations. TDP-43_SAA can detect misfolded TDP-43 also in the CSF of presymptomatic individuals. In both groups, most TDP-43_SAA positive cases were carriers of GRN mutation. Two GRN carriers that resulted TDP-43_SAA positive converted to the symptomatic phase of the disease.

MeSH

Dementia, Frontotemporal Dementia, Alzheimer Disease, Seeds, Amyotrophic Lateral Sclerosis, Mutation